Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH:10]=[C:11]3[N:17]([N:18]=2)[C:16]2[CH:19]=[C:20]([C:23](O)=[O:24])[CH:21]=[CH:22][C:15]=2[O:14][CH2:13][CH2:12]3)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[NH2:32][C:33]1[CH:37]=[CH:36][O:35][N:34]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(Cl)Cl.CN(C=O)C>[CH:1]([N:4]1[C:8]([C:9]2[CH:10]=[C:11]3[N:17]([C:16]4[CH:19]=[C:20]([C:23]([NH:32][C:33]5[CH:37]=[CH:36][O:35][N:34]=5)=[O:24])[CH:21]=[CH:22][C:15]=4[O:14][CH2:13][CH2:12]3)[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: Nc1ccon1
Reactant: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C(=O)O)ccc1OCC2
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C(=O)Nc3ccon3)ccc1OCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice-cooled suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carboxylic acid (0.15 g, 0.44 mmol) in DCM (3.5 mL) was added oxalyl chloride (79 L, 0.93 mmol) and DMF (25 L) and the mixture stirred at RT for 2 h. 3-Amino-isoxazole (185 mg, 2.2 mmol) and triethylamine (0.12 mL, 0.88 mmol) were added and the mixture stirred at RT for 18 h before the addition of saturated aqueous sodium hydrogen carbonate. The resultant mixture was extracted with DCM then 5% MeOH in DCM and the combined extracts dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% MeOH in DCM) followed by trituration in diethyl ether to give 126 as a white solid. 1H NMR (CDCl3, 400 MHz): δ 9.49 (s, 1 H); 8.65 (d, J=2.3 Hz, 1 H); 8.30 (d, J=1.8 Hz, 1 H); 7.96 (d, J=0.7 Hz, 1 H); 7.86 (dd, J=8.5, 2.3 Hz, 1 H); 7.30 (d, J=8.5 Hz, 1 H); 7.23 (d, J=1.8 Hz, 1 H); 6.88 (s, 1 H); 5.72-5.59 (m, 1 H); 4.61 (t, J=5.6 Hz, 2 H); 3.25 (t, J=5.6 Hz, 2 H); 1.58 (d, J=6.6 Hz, 6 H). LCMS: RT=10.24 min, M+H+=406
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:23](O)([CH3:26])([CH3:25])[CH3:24].N12CCCN=C1CCCCC2>CN(C)C=O.O>[C:23]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)O
Reactant: O=C(O)c1cccc(I)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CC(C)(C)OC(=O)c1cccc(I)c1
Temperature: 40 °C
Yield: 92.1 %

Procedure:
To a solution of 3-iodobenzoic acid (50 g, 0.2 mol) in N,N-dimethylformamide (250 mL) was added solid 1,1′-carbonyldiimidazole (32.4 g, 0.2 mol) over 15 min. The resulting mixture was heated at 40° C. for 1 hr, then was added tert-butyl alcohol (29.6 g, 0.4 mol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (30.4 g, 0.2 mol) and heated at 40° C. overnight. The reaction was cooled to room temperature, diluted with water (500 mL) and extracted with hexane (2×500 mL). The combined organic layers were washed with water (2×400 mL), brine (250 mL), dried over anhydrous magnesium sulfate (15 g), filtered and concentrated under reduced pressure to give the title compound (56 g, 92%) as an oil. NMR 60 MHz, (CDCl3), δ 8.3 (m, 1H), 7.8 (m, 2H), 7.0 (m, 1H), 1.6 (s, 9H).
Reaction SMILES: [N+](=[CH:3][C:4](=[O:9])[CH2:5][CH2:6][CH:7]=[CH2:8])=[N-].[C:10]([OH:13])(=[O:12])[CH3:11]>>[C:10]([O:13][CH2:3][C:4](=[O:9])[CH2:5][CH2:6][CH:7]=[CH2:8])(=[O:12])[CH3:11]
Reactant: CC(=O)O
Reactant: C=CCCC(=O)C=[N+]=[N-]
Product: C=CCCC(=O)COC(C)=O
Yield: 90 %

Procedure:
Into 35 ml of glacial acetic acid at 60°-70° C. is dropped slowly 12.4 g. (0.1 mole) of 1-diazo-5-hexen-2-one. After the nitrogen evolution stops, the reaction mixture is heated to reflux for one hour. The resulting mixture is extracted with 3×50 ml of methylene chloride. The organic layer is dried over anhydrous magnesium sulfate. Concentration of the filtrate gives 1-acetoxy-5-hexen-2-one as a brown oil in 90% yield, based on the starting 4-pentenoyl chloride. ##STR40##
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([O:17]CCC)=O.[NH2:21][C:22]1[CH:27]=[N:26][CH:25]=[C:24]([Cl:28])[N:23]=1>>[Cl:28][C:24]1[N:23]=[C:22]([NH:21][C:15]([C:3]2[N:4]([CH3:14])[S:5](=[O:12])(=[O:13])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:2]=2[OH:1])=[O:17])[CH:27]=[N:26][CH:25]=1
Reactant: CCCOC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Reactant: Nc1cncc(Cl)n1
Product: CN1C(C(=O)Nc2cncc(Cl)n2)=C(O)c2ccccc2S1(=O)=O

Procedure:
This compound was prepared from propyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide and 2-amino-6-chloro-pyrazine analogous to Example 1.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](=[C:13](SC)SC)[C:11]#[N:12].[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O.[NH2:27][NH2:28]>C(O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:12])=[N:27][NH:28][C:13]=1[NH:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CSC(SC)=C(C#N)c1nc2ccccc2s1
Reactant: NN
Reactant: NCc1ccccc1
Solvent: O
Solvent: CCO
Product: Nc1n[nH]c(NCc2ccccc2)c1-c1nc2ccccc2s1
Temperature: 25 °C
Yield: 52.9 %

Procedure:
A solution of 2-benzothiazol-2-yl-3,3-bismethylsulfanylacrylonitrile (200 mg, 0.73 mmol) and benzylamine (160 mg, 1.5 mmol) in 50 mL of ethanol was heated to reflux for 90 minutes. Hydrazine hydrate (35 μL, 1.0 mmol) was then added to the reaction mixture. The solution was heated to reflux until the reaction was complete as determined by TLC analysis. The reaction solution was allowed to cool to room temperature and the title compound (124 mg) was isolated by filtration, washed with ethanol and dried under high vacuum. MS (m/z, ES+): 322 (M+1, 100%); 1H NMR (300 MHz, ppm, DMSO-d6): δμ11.32 (br s, 1/3H), 10.89 (s, br., 2/3H), 7.98 (d, 3J=7.7 Hz, 1H), 7.82 (d, 3J=8.0 Hz, 1H), 7.41-7.28 (m, 6H), 7.22 (m, 1H), 6.15 (br s, 9/10H), 4.95 (br s, 1/10H), 4.48 (d, 3J=4.7 Hz, 1H). Yield=53%.
Reaction SMILES: [F:1][C:2]1[C:10]2[C:6](=[C:7]([CH3:12])[N:8]([CH3:11])[N:9]=2)[CH:5]=[C:4](C(O)=O)[C:3]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=1[F:24].C([N:27]([CH2:30]C)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:39])C=CC=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[C:10]2[C:6](=[C:7]([CH3:12])[N:8]([CH3:11])[N:9]=2)[CH:5]=[C:4]2[NH:27][C:30](=[O:39])[N:16]([C:17]3[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=3[F:24])[C:3]=12
Reactant: CCN(CC)CC
Reactant: Cc1c2cc(C(=O)O)c(Nc3ccc(I)cc3F)c(F)c2nn1C
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1c2cc3[nH]c(=O)n(-c4ccc(I)cc4F)c3c(F)c2nn1C
Temperature: 25 °C
Yield: 40 %

Procedure:
To a suspension of 7-fluoro-6-(2-fluoro-4-iodophenylamino)-2,3-dimethyl-2H-indazole-5-carboxylic acid (126 mg, 0.29 mmol) in toluene (10 ml) was added triethylamine (0.13 ml, 0.90 mmol) and diphenylphosphoryl azide (0.081 ml, 0.38 mmol). The reaction was heated at reflux for 4 h. The mixture was cooled to room temperature and concentrated to dryness. Silica gel chromatography (EtOAc:Hexane=75:25) yields 51 mg (39%) of the title compound as a light yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1.[I-:18].[Na+].O>CC(=O)CC>[I:18][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1
Reactant: ClCCOc1ccc(Cc2ccccc2)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCC(C)=O
Product: ICCOc1ccc(Cc2ccccc2)cc1
Yield: 72.9 %

Procedure:
A solution of 1-(2-chloroethoxy)-4-(benzyl)benzene (734 mg, 2.97 mmol) and sodium iodide (1.78 g, 11.9 mmol) in 2-butanone (30 mL) was heated at reflux for 16 hours. After cooling, water was added. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Flash chromatography gave 732 mg of 1-(2-iodoethoxy)-4-(benzyl)benzene, 1H NMR (300 MHz, CDCl3) δ 7.29 (dd, 2H), 7.19 (dd, 1H), 7.18 (d, 2H), 7.11 (d, 2H), 6.84 (d, 2H), 4.23 (t, 2H), 3.94 (s, 2H), 3.41 (t, 2H) ppm.
Reaction SMILES: F[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2[O:11]C(N)=[N:9][N:8]=2)=[CH:4][CH:3]=1.NN.[OH2:17]>>[OH:17][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]([NH:8][NH2:9])=[O:11])=[CH:4][CH:3]=1
Reactant: O
Reactant: Nc1nnc(Cc2ccc(F)cc2)o1
Agent: NN
Product: NNC(=O)Cc1ccc(O)cc1
Temperature: 195 °C

Procedure:
A mixture of 5-(4-fluoro-benzyl)-[1,3,4]oxadiazol-2-ylamine 10.182 g (52.7 mmol), water 80 mL and anhydrous hydrazine 20 mL was refluxed under nitrogen on an oil bath (190-200 ° C.) for 23 hours. The mixture was cooled and allowed to crystallize at R.T. under nitrogen overnight. The precipitated product was collected by filtration, washed with ice-cold water (10 mL) and dried on high vacuum. The crude product was re-crystallized from water 60 mL (reflux under nitrogen, than to +4° C. in a refrigerator overnight). The product was filtered, washed with ice-cold water and dried on high vacuum. Y=6.210 g (56.5%) of a large white crystals. 1H-NMR(DMSO-d6, 400 MHz): 7.267 (app d, J=8.6 Hz, J=5.5 Hz, 2H), 7.097 (app t, J=9.0 Hz, 2H), 5.509 (br s, 2H), 5.339 (s, 2H), 3.884 (s, 2H); 19F-NMR(DMSO-d6, 376.5 MHz): −117.14 (m, 1F).
Reaction SMILES: [CH:1]1([N:4]([CH3:13])[S:5]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[O:14](C)[S:15]([C:18]([F:21])([F:20])[F:19])(=[O:17])=[O:16]>>[F:19][C:18]([F:21])([F:20])[S:15]([O-:17])(=[O:16])=[O:14].[CH:1]1([N:4]([CH3:13])[S:5]([N:8]2[CH:12]=[CH:11][N+:10]([CH3:18])=[CH:9]2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: CN(C1CC1)S(=O)(=O)n1ccnc1
Reactant: COS(=O)(=O)C(F)(F)F
Product: CN(C1CC1)S(=O)(=O)n1cc[n+](C)c1
Product: O=S(=O)([O-])C(F)(F)F

Procedure:
3-(Cyclopropyl-methyl-sulfamoyl)-1-methyl-3-H-imidazol-1-ium trifluoromethane-sulfonate was prepared in accordance with step B of the general method described in example 76 from imidazole-1-sulfonic acid cyclopropyl-methyl-amide and methyl triflate; MS: m/e=216.4 (M+).
Reaction SMILES: C([O:20][CH2:21][C@H:22]1[O:26][C@@H:25]([N:27]2[CH:34]=[CH:33][C:31](=[O:32])[NH:30][C:28]2=[O:29])[CH:24]=[CH:23]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C(Cl)(Cl)Cl.CO>[C@@H:25]1([N:27]2[CH:34]=[CH:33][C:31](=[O:32])[NH:30][C:28]2=[O:29])[O:26][C@H:22]([CH2:21][OH:20])[CH:23]=[CH:24]1
Reactant: O=c1ccn([C@H]2C=C[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=c1ccn([C@H]2C=C[C@@H](CO)O2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
5'O-trityl-2',3'-dideoxy-2',3'-didehydrouridine (0.5 gm.,1.1 mM) was dissolved in a chloroform (10 mL) and methanol (2 mL) mixture containing 2% p-toluenesulphonic acid. The reaction mixture was stirred at room temperature for 0.75 hr., and then neutralized with 2N NaOH (0.5 mL). The solvent was removed in vacuo and the residue chromatographed on silica using chloroform/acetone (2:1) as eluent. The desired product was isolated as a white crystalline solid with the same physical and spectroscopic characteristics as d4U produced by an alternative method. M.p. 155° C. 1H NMR (360 Mhz, D2O/DMSO) 7.8 (d, 1H, H6), 6.7 (m, 1H, H1'), 6.37 (m, 1H, H2'), 5.8 (m, 1H, H3'), 5.56 (d, 1H, H5), 4.7 (m, 1H, H4'), 3.6 (m, 2H, H5'). 13C NMR (70 Mhz, D2O/DMSO) 163 (C4), 151 (C2), 141 (C2'), 135 (C3'), 126 (C6), 101 (C5), 89 (C1'), 87 (C4'), 62 (C5').
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([CH:19]([CH3:21])[CH3:20])[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)=[N:7]2.[Cl:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[N:25]=[C:26]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=1)[C:27]([CH:33]([CH3:35])[CH3:34])=[N:28]2.[Br:43]N1C(C)(C)C(=O)N(Br)C1=O.C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:43][C:19]([C:5]1[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[N:7][C:8]2[C:3]([N:4]=1)=[C:2]([Cl:1])[CH:11]=[CH:10][CH:9]=2)([CH3:21])[CH3:20].[Br:43][C:33]([C:27]1[C:26]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=2)=[N:25][C:24]2[C:29](=[CH:30][CH:31]=[CH:32][C:23]=2[Cl:22])[N:28]=1)([CH3:35])[CH3:34]
Reactant: CC(C)c1nc2cccc(Cl)c2nc1-c1cccc(F)c1
Reactant: CC(C)c1nc2c(Cl)cccc2nc1-c1cccc(F)c1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(Br)c1nc2c(Cl)cccc2nc1-c1cccc(F)c1
Product: CC(C)(Br)c1nc2cccc(Cl)c2nc1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 5-chloro-2-(3-fluorophenyl)-3-isopropylquinoxaline and 5-chloro-3-(3-fluorophenyl)-2-isopropylquinoxaline (3.3042 g, 10.99 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (4.712 g, 16.48 mmol) were suspended in carbon tetrachloride (109.9 mL, 10.99 mmol). To the mixture was added benzoyl peroxide (0.3548 g, 1.099 mmol) and the mixture was heated at reflux. After 20 h, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 120 g of Redi-Sep™ column using 0 to 10% gradient of EtOAc in hexane over 15 min and then 10% isocratic of EtOAc for 30 min as eluent to give 3-(2-bromopropan-2-yl)-5-chloro-2-(3-fluorophenyl)quinoxaline and 2-(2-bromopropan-2-yl)-5-chloro-3-(3-fluorophenyl)quinoxaline as a yellow solid: LC-MS (ESI) m/z 379.0 and 381.0 [M+H]+. The mixture of two regioisomers was carried as a mixture without further purification for the next step.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH:13](O)[CH3:14].[OH-:16].[K+]>C(O)C>[OH:16][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(O)OCCOCCCl
Reactant: C1CCNC1
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: OCCOCCOCCN1CCCC1
Yield: 76 %

Procedure:
A total of 295 g of pyrrolidine and 250 g of 2-chloroethoxyethoxyethanol in 750 ml of ethanol was refluxed for 5 hours. The reaction mixture was then treated with 106 g of KOH and refluxed for an additional hour. Filtration and distillation yielded 229 g of N-(hydroxyethoxyethoxyethyl)pyrrolidine (b.p.=145° C. at 3 mm).
Reaction SMILES: [CH3:1][CH:2]([OH:5])[CH:3]=[CH2:4].C(N(CC)CC)C.[Cl:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]([CH2:24][O:25][C:26]3[CH:48]=[CH:47][C:29]4[O:30][CH2:31][C:32]5[CH:45]=[C:44](I)[CH:43]=[CH:42][C:33]=5[CH:34]([O:35][CH:36]5[CH2:41][CH2:40][CH2:39][CH2:38][O:37]5)[C:28]=4[CH:27]=3)=[N:21]2)=[CH:16][C:15]=1[F:49].C(Cl)Cl>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]([CH2:24][O:25][C:26]3[CH:48]=[CH:47][C:29]4[O:30][CH2:31][C:32]5[CH:45]=[C:44]([CH2:4][CH2:3][C:2](=[O:5])[CH3:1])[CH:43]=[CH:42][C:33]=5[CH:34]([O:35][CH:36]5[CH2:41][CH2:40][CH2:39][CH2:38][O:37]5)[C:28]=4[CH:27]=3)=[N:21]2)=[CH:16][C:15]=1[F:49]
Reactant: Fc1cc2ccc(COc3ccc4c(c3)C(OC3CCCCO3)c3ccc(I)cc3CO4)nc2cc1Cl
Reactant: C=CC(C)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClCCl
Product: CC(=O)CCc1ccc2c(c1)COc1ccc(OCc3ccc4cc(F)c(Cl)cc4n3)cc1C2OC1CCCCO1
Temperature: 0 °C
Yield: 61.3 %

Procedure:
0.2 g of (±)-3-buten-2-ol, 1.4 mg of palladium (II) acetate and 0.27 g of triethylamine were added to 1.36 g of 2-(7-chloro-6-fluoroquinolin-2-yl)methoxy-8-iodo-11-(2-tetrahydropyranyloxy)-6,11-dihydrodibenz[b,e]oxepine obtain in Reference example 73 dissolved in 2.5 ml of acetonitrile and the mixture was refluxed under heating for 5.5 hours. After 60 ml of methylene chloride and 60 ml of ice water were added to this reaction mixture, the organic layer was separated, washed with water and dried over anhydrous sodium sulfate. After the solvent was removed, the residue was applied to silica gel column chromatography to obtain 0.76 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)[C:5]([F:21])=[CH:4][C:3]=1[NH:22][C:23]([C:25]1([C:28]([O:30]C)=[O:29])[CH2:27][CH2:26]1)=[O:24].O.O.[OH-].[Li+:35]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)[C:5]([F:21])=[CH:4][C:3]=1[NH:22][C:23]([C:25]1([C:28]([O-:30])=[O:29])[CH2:27][CH2:26]1)=[O:24].[Li+:35]
Reactant: COC(=O)C1(C(=O)Nc2cc(F)c(Oc3ccnc(-c4cnn(C)c4)c3)cc2F)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2cc(Oc3cc(F)c(NC(=O)C4(C(=O)[O-])CC4)cc3F)ccn2)cn1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 89.8 %

Procedure:
To a suspension of methyl 1-((2,5-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)carbamoyl)cyclopropanecarboxylate (5.8 g, 13.54 mmol) in THF (100 mL) were added water (50.0 mL) and lithium hydroxide monohydrate (2.84 g, 67.7 mmol). The reaction mixture was stirred at RT for 40 minutes. The layers were separated and the organic phase washed with brine (50 mL), dried (MgSO4) and concentrated to dryness to afford lithium 1-((2,5-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)carbamoyl)cyclopropanecarboxylate (5.11 g, 86% yield) as an off-white foam. MS (ESI): m/z 415.1 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[O:5][C:4](=[O:12])[CH:3]=1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH2:30][CH2:31][NH:32][C:33](=[O:35])[CH3:34])=[CH:22]1>>[OH:1][C:2]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[O:5][C:4](=[O:12])[C:3]=1[CH:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:22]1[NH:21][C:29]2[C:24]([C:23]=1[CH2:30][CH2:31][NH:32][C:33](=[O:35])[CH3:34])=[CH:25][CH:26]=[CH:27][CH:28]=2
Reactant: O=Cc1ccccc1
Reactant: CC(=O)NCCc1c[nH]c2ccccc12
Reactant: O=C1C=C(O)C2(CCCCC2)O1
Product: CC(=O)NCCc1c(C(C2=C(O)C3(CCCCC3)OC2=O)c2ccccc2)[nH]c2ccccc12

Procedure:
Using general procedure C, 4-hydroxy-1-oxa-spiro[4.5]dec-3-en-2-one (Lit. 15) was reacted with benzaldehyde and N-[2-(1H-indol-3-yl)-ethyl]-acetamide to give the title compound as a white solid. MS: 459.1 ([M+H]+).
Reaction SMILES: [CH3:1][N:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)[Cl:36]>>[CH3:1][N:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][Cl:36])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClCCl
Reactant: CN(CCCCCCO)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CN(CCCCCCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1H-NMR (CDCl3,ppm) δ: 1.31-1.42(4 H,m), 1.51-1.63(4 H,m), 2.91(3 H,s), 3.30(2 H,t,J=7.9 Hz), 3.63(2 H,t,J=6.6 Hz), 6.64-6.70(3 H,m), 7.18-7.21(2 H,m) 6-(N-Methy-N-phenylamino)hexyl alcohol (1.1 g) and triphenylphosphine (1.3 g) were dissolved in methylene chloride (40 ml), and N-chlorosuccinylimide (0.71 g) was added, which was followed by stirring at room temperature for 1 hr 20 min. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 0.90 g of 6-(N-methy-N-phenylamino)hexyl chloride.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([NH:12][OH:13])=[NH:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH:14]1([C:20]([Cl:22])=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[ClH:22].[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[N:11]=[C:20]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[O:13][N:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(C(=N)NO)CC1
Reactant: O=C(Cl)C1CCCCC1
Product: CC(C)N1CCC(c2noc(C3CCCCC3)n2)CC1
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 56, starting from 1-isopropyl-N-hydroxypiperidine-4-carboxamidine and cyclohexanecarbonyl chloride.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[S:8][C:9]2[C:10]([CH2:15][S:16][CH2:17][CH2:18][NH:19]C(OC(C)(C)C)=O)=[N:11][CH:12]=[CH:13][CH:14]=2)C=CC=CC=1.C([SiH](CC)CC)C.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]>ClCCl>[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49].[SH:8][C:9]1[C:10]([CH2:15][S:16][CH2:17][CH2:18][NH2:19])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCCSCc1ncccc1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCSCc1ncccc1S
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Into a 1 L round bottom flask equipped with a mechanical stirrer, thermometer and nitrogen purge was charged 3-triphenylmethylthio-2-(t-butoxycarbonylaminoethylthiomethyl)pyridine (40.0 g, 0.074 mol, 1 eq) followed by dichloromethane (200 mL). The light yellow solution was cooled to 0° C. and triethylsilane (60 mL) was added followed by dropwise addition of trifluoroacetic acid (200 mL) over approximately five minutes. The cold bath was removed and the solution was allowed to warm to room temperature (over 30 minutes) and was then allowed to stir at 20° C. for 30 minutes. The solvent was removed by rotary evaporation to give 27.75 g of the title compound as an orange waxy solid. 1H NMR (D2O) δ 2.88 (t, 2H); 3.28 (t, 3H); 4.18 (s, 2H); 7.45 (dd, 1H); 8.22 (d, 1H); 8.55 (d, 1H).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]1([N:15]=[C:16]=[N:17][CH:18]2[CH2:23]CCC[CH2:19]2)[CH2:14]CCC[CH2:10]1>>[CH:18]([NH:17][C:16](=[N:15][CH:9]([CH3:14])[CH3:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:23])[CH3:19]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: OCc1ccccc1
Product: CC(C)N=C(NC(C)C)OCc1ccccc1

Procedure:
Synthesis is carried out from benzyl alcohol and N,N′-dicyclohexylcarbodiimide (Mathias, Synthesis 1979, 561.)
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH:9]1([C:12]([C:14]2[O:15][C:16]3[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[CH:19][C:17]=3[CH:18]=2)=[O:13])[CH2:11][CH2:10]1.O>C(#N)C>[Br:1][C:19]1[C:17]2[CH:18]=[C:14]([C:12]([CH:9]3[CH2:10][CH2:11]3)=[O:13])[O:15][C:16]=2[C:22]([O:23][CH3:24])=[CH:21][CH:20]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc2cc(C(=O)C3CC3)oc12
Solvent: CC#N
Solvent: O
Product: COc1ccc(Br)c2cc(C(=O)C3CC3)oc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.3 %

Procedure:
N-bromosuccinimide (0.21 g) was added in a single portion to a stirred solution of cyclopropyl-(7-methoxybenzofuran-2-yl)-methanone (0.25 g) in acetonitrile (20 ml) under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 24 h. Water (20 ml) was added, the mixture extracted with ethyl acetate (100 ml), the organic layer separated, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography on silica eluting with 5-10% ethyl acetate in hexane afforded the title compound as an off-white solid (0.24 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[CH2:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH3:7].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:5][CH2:4][CH2:3][CH2:2][N:8]([CH2:6][CH3:7])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCNCC
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCCCCCN(CC)CCCCl
Yield: 44 %

Procedure:
A mixture of 30 g 0.19 mole) of 1-bromo-3-chloropropane, 25 g (0.17 mole) of ethylheptylamine, 28 g (0.20 mole) of potassium carbonate and 250 ml of toluene was refluxed for 8 hours. After cooling, the solid was collected by filtration, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) to give 17 g of the desired compound (yield 44%).
Reaction SMILES: [CH:1]1[CH2:5]C=[CH:3][CH:2]=1.[C:6]([O:9][CH2:10][CH:11]=[C:12]([CH:14]=[O:15])[CH3:13])(=[O:8])[CH3:7].[C:16]1(C=CC(O)=CC=1)O>>[C:6]([O:9][CH2:10][CH:11]1[C:12]([CH3:16])([CH:14]=[O:15])[CH:13]2[CH2:3][CH:2]1[CH:1]=[CH:5]2)(=[O:8])[CH3:7]
Reactant: CC(=O)OCC=C(C)C=O
Reactant: Oc1ccc(O)cc1
Reactant: C1=CCC=C1
Product: CC(=O)OCC1C2C=CC(C2)C1(C)C=O
Yield: 62 %

Procedure:
66 g (1 mole) of freshly distilled cyclopentadiene, 71 g (0.5 mole) of 3-formyl-crotyl acetate and 1 g of hydroquinone were heated for 10 hours at 160° C. under nitrogen in a 1 liter stirred autoclave. The reaction mixture was then subjected to fractional distillation, given 65 g of the product (yield: 62%).